IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT

赞助:

合作者:

信息的提供 (责任方):

Naoyuki G. Saito, M.D., Ph.D.，Indiana University School of Medicine

追踪信息

首次提交日期 ^ICMJE

October 2, 2018

首次发布日期e ^ICMJE

October 4, 2018

最后更新发布日期

October 4, 2018

预计研究开始日期 ^ICMJE

August 29, 2018

预计主要完成日期

March 31, 2023 (主要结果测量的最终数据收集日期)

目前主要观察指标 ^ICMJE

Dose limiting toxicity (DLT) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine[ Time Frame: Day -7 of conditioning regimen through 30 days post transplant (37 days) ]

Maximum-tolerated dose (MTD) of Total Marrow Irradiation (TMI) in combination with 150 mg/m2 fludarabine[ Time Frame: Day -7 of conditioning regimen through 30 days post transplant (37 days) ]

Overall survival (OS) rate 1 year post transplant[ Time Frame: 1 year ]

原始主要观察测量 ^ICMJE

与当前相同

目前的二级观察 ^ICMJE

Frequency of non hematologic toxicities[ Time Frame: 100 days ]
Incidence of infection[ Time Frame: 100 days ]
Type of infections[ Time Frame: 100 days ]
Incidence of graft versus host disease (GvHD)[ Time Frame: 100 days ]
Incidence of chronic graft versus host disease (GvHD)[ Time Frame: 3 years ]
Incidence of sinusoidal obstruction syndrome (SOS)[ Time Frame: 100 days ]
Incidence of pneumonitis[ Time Frame: 100 days ]
Incidence of mucositis[ Time Frame: 100 days ]
Time to engraftment of neutrophils[ Time Frame: from date of transplant to the first of three consecutive days after transplantation during which the absolute neutrophil count (ANC) is greater than or equal to 0.5 x 10^9/liter ]
Time to engraftment of platelets[ Time Frame: from date of transplant until he first of seven consecutive days after transplantation during which the platelet count is greater than or equal to 20 x10^9/liters without transfusion. ]
Disease response rate[ Time Frame: Day 30 after transplant (30 days) ]
Incidence of relapse mortality[ Time Frame: 30 days ]
Incidence of relapse mortality[ Time Frame: 100 days ]
Incidence of relapse mortality[ Time Frame: 1 year ]
Incidence of non-relapse mortality[ Time Frame: 30 days ]
Incidence of non-relapse mortality[ Time Frame: 100 days ]
Incidence of non-relapse mortality[ Time Frame: 1 year ]
Disease-Free Survival[ Time Frame: 3 years ]

描述性信息

简略标题 ^ICMJE

IMRT-TMI With Fludarabine as Myeloablative Conditioning for Allogeneic HSCT

正式标题 ^ICMJE

A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) With Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies

简要概况

The purpose of this study is to find the maximum tolerated dose (MTD) of Total Marrow Irradiation (TMI), a type of radiation treatment administered with fludarabine, a type of chemotherapy to prepare patients for allogeneic hematopoietic stem cell transplantation (Allo-HSCT). The study will also examine the efficacy of fludarabine and total marrow radiation treatment. Patients in this study will receive fludarabine and TMI during their conditioning regimen for 7 days prior to Allo-HSCT

详细说明

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of intensity modulated radiation therapy based total marrow irradiation (TMI) in combination with fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (Allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk and relapsed or refractory leukemia and myelodysplasia. TMI, which allows for conformal dosing of target bone marrow tissue while giving lower doses to organs at risk, is considered by many to be a superior alternative to conventional total body irradiation (TBI) Primary Objectives: Phase I component: Determine the MTD of TMI given concurrently with fludarabine (fixed at 150 mg/m2) as a conditioning regimen for Allo-HSCT for patients with high risk (relapsed/refractory) acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelogenous leukemia (CML). Phase II component: Single-arm exploratory study to expand the cohort at the MTD level to estimate 1- year overall survival (OS), with the objective of increasing the OS from the historical rate of 30% (null hypothesis ) to 50% (alternate hypothesis) with 80% power and a one-sided type I error of 0.05. Secondary Objectives 1. Describe the extramedullary toxicity and the incidence of complications, including mucositis, acute and chronic graft versus host disease (GvHD), sinusoidal obstruction syndrome (SOS), and pneumonitis. 2. Describe the time to engraftment of neutrophils and platelets 3. Describe the disease response rate at day 30 after transplantation 4. Describe the overall survival and disease-free survival 5. Describe the cumulative incidence of relapse and non-relapse mortality 6. Determine the correlation between plasma/serum markers and radiation induced acute and long term toxicities.

研究类型 ^ICMJE

Interventional

研究阶段

Phase 1/Phase 2

研究设计 ^ICMJE

分配:
干预模型: Sequential Assignment
干预模型描述: Standard "3+3" phase I design of dose escalation using 3 patients per dose level cohort with an expansion to 6 patients at the MTD will be used during the phase 1 component. We will treat 3 patients at the initial dose level of TMI. If no dose-limiting toxicity [DLT] is observed, the next cohort of three patients is treated at the next higher dose level. If 1 of the 3 patients demonstrates DLT, an additional 3 patients are treated at that dose level. If only 1 of the 6 shows DLT, the next cohort of three patients is entered at the next dose level. If 2 or more of the 6 demonstrate DLT, the MTD is defined as the previous dose level. If no DLT is observed in the final dose level, the number of patients treated will be expanded to 6. The phase II component will enroll additional patients at the defined MTD level.
盲法: Interventional
盲法描述:
主要目的: Treatment

适用条件 ^ICMJE

干预项目 ^ICMJE

Drug: Fludarabine
Fludarabine 30 mg/m2/day IV (total 5 doses) administered days -7 through -3 of conditioning regimen
Radiation: Total Marrow Irradiation (TMI)
TMI will be delivered twice a day, at least 6 hours apart, on days -7 through -3 (total of 10 fractions) of conditioning regimen

研究工具

Experimental: Fludarabine + Total Marrow Irradiation

招募信息

招募状态 ^ICMJE

Recruiting

预计入组 ^ICMJE

原始预计入组 ^ICMJE

与当前相同

预计研究完成日期

March 31, 2024

预计主要完成日期

March 31, 2023 (主要结果测量的最终数据收集日期)

合格标准 ^ICMJE

Inclusion Criteria: 1. Patients must be diagnosed with one of the following conditions: Acute Myeloid Leukemia (AML) who are not in complete remission, and who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors: 1. Duration of first CR < 6 months (if previously in CR) 2. Poor risk karyotype including any of the following: complex karyotype with ≥3 clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q abnormalities, t(6;9), t(9;22), 17p abnormalities [or TP53 mutations] or monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used for eligibility criteria determination. 3. Circulating peripheral blood blasts at time of enrollment 4. Karnofsky performance status <90% Acute Lymphocytic Leukemia (ALL) who are not in complete remission, and who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors: 1. First refractory relapse. Patients in second or subsequent relapse are excluded. 2. Donor is CMV seropositive 3. Bone marrow blasts >25% (within 30 days of admission) 4. Age >40 years Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than 4.5 (i.e., high- or very-high risk). Chronic Myelogenous Leukemia (CML) in either 1. Accelerated phase, defined by any of the following: - Blasts 10-19% in peripheral blood white cells or bone marrow - Peripheral blood basophils at least 20% - Persistent thrombocytopenia (<100 x 109/l) unrelated to therapy, or persistent thrombocytosis (>1000 x 109/l) unresponsive to therapy - Increasing spleen size and increasing white blood cell (WBC) count unresponsive to therapy - Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase) 2. Chronic phase provided a complete hematologic remission was not achieved by 3 months or a complete cytogenetic remission by 18 months and the patient had received at least 2 tyrosine kinase inhibitors. 2. Patient age 18-65 years 3. Availability of a consenting human leukocyte antigens(HLA) -matched donor 4. Karnofsky Performance Status 70% or higher 5. Required baseline laboratory values: 1. Estimated creatinine clearance ≥ 60 ml/min 2. Aspartate aminotransferase and alanine aminotransferease ≤ 2.5 x upper limit of normal value 3. Bilirubin ≤ 1.5 x upper limit of normal value 6. Required baseline cardiac function of left ventricular ejection fraction (LVEF) > 45 % corrected 7. Required baseline pulmonary function of lung diffusing capacity (DLCO) > 45 % predicted (corrected for hemoglobin) 8. Patient must be capable of understanding the investigational nature of this study, potential risks and benefits of the study, and be able to provide a valid informed consent. Exclusion Criteria: 1. Patients with ALL who are in second or subsequent relapse 2. Active infection: Patients with active infections requiring oral or intravenous antimicrobial drugs are not eligible for enrollment until resolution of infection. 3. HIV seropositive patients. 4. Pregnant or nursing females are excluded from this study. 5. Prior radiation therapy 6. Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation

性别

参与研究的性别:

All

年龄

最小年龄：18 Years ，最大年龄：65 Years

接受健康的志愿者

没有

可入组国家 ^ICMJE

United States

管理信息

数据检测委员会

Yes

研究涉及美国FDA监管的产品

研究美国FDA监管的药品: Yes
研究涉及美国FDA监管的设备产品: No

IPD 共享声明

计划分享 IPD:

责任方

Naoyuki G. Saito, M.D., Ph.D.，Indiana University School of Medicine

研究赞助商 ^ICMJE

Naoyuki G. Saito, M.D., Ph.D.

合作者 ^ICMJE

研究员 ^ICMJE

Principal Investigator: Naoyuki G Saito, MD PhD Indiana University

PRS 账户

Indiana University School of Medicine

验证日期

October 2018

^ICMJE 国际医学期刊编辑委员会和世界卫生组织 ICTRP 要求的元素

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